Pyruvate Kinase M2 Regulates Gene Transcription by Acting as a Protein Kinase

Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
Molecular cell (Impact Factor: 14.02). 02/2012; 45(5):598-609. DOI: 10.1016/j.molcel.2012.01.001
Source: PubMed


Pyruvate kinase isoform M2 (PKM2) is a glycolysis enzyme catalyzing conversion of phosphoenolpyruvate (PEP) to pyruvate by transferring a phosphate from PEP to ADP. We report here that PKM2 localizes to the cell nucleus. The levels of nuclear PKM2 correlate with cell proliferation. PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor. ADP competes with the protein substrate binding, indicating that the substrate may bind to the ADP site of PKM2. Our experiments suggest that PKM2 dimer is an active protein kinase, while the tetramer is an active pyruvate kinase. Expression of a PKM2 mutant that exists as a dimer promotes cell proliferation, indicating that protein kinase activity of PKM2 plays a role in promoting cell proliferation. Our study reveals an important link between metabolism alteration and gene expression during tumor transformation and progression.

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Available from: Xueliang Gao, Feb 03, 2015
    • "phosphorylated in response to growth factors, PKM2 may undergo a switch in both oligomerization state (from a tetramer to a dimer) and catalytic function (from its glycolytic role to a protein kinase), and affect transcription by phosphorylating both histones (e.g., T11 on histone H3, which promotes acetylation at K9, a modification that stimulates transcription) (Yang et al. 2012) and transcription factors (e.g., Y705 in STAT3, which promotes its dimerization and transactivator function) (Gao et al. 2012). "
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    • "For instance, the M2 isoform of pyruvate kinase (PKM2), which forms a tetramer in the cytosol, is the final key enzyme in aerobic glycolysis. However , PKM2 can translocate into the nucleus to act as a protein kinase in its dimeric form and phosphorylate signal transducer and activator of transcription 3 (Gao et al., 2012) or to directly interact with HIF1-a to promote downstream target transactivation (Luo et al., 2011). The possibilities of different subcellular localizations, conformations, and nonenzymatic functions of ME are worthy of further investigation. "
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    • "Given the unabated rate of progress since its discovery more than 30 years ago, we are certainly in for more surprises and insights, and undoubtedly, this will require the development of new technologies. It seems unlikely that additional dedicated TKs will be identified, but the recent report that PKM2 can phosphorylate STAT3 on Tyr705 (Gao et al. 2012) means that other enzymes that use ATP, or another substrate with an energy-rich phosphate, might also moonlight as TKs under special circumstances . Likewise, additional P.Tyr phosphatase activities may emerge; a recent example is STS- 1, a member of the histidine phosphatase family that has been reported to be a P.Tyr phosphatase (Mikhailik et al. 2007). "
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